Biology subjects

Herrero, M.

Publications and source records attributed to Herrero, M..

6 recordsLinked to original sources

bioRxiv2026

Cell-state mapping reveals a reversible neuroblast accumulation in the aging mouse hippocampus

Hippocampal neurogenesis supports learning and memory by generating new granule cells throughout life. However, both the rate and speed of this process decline with age. To elucidate the molecular determinants underlying the effects of aging on neuronal differentiation, we combined lineage tracing of adult-born granule cells (aGCs) with single-nucleus RNA sequencing. This approach produced a temporally resolved transcriptional atlas of aGC development. Aging led to a marked accumulation of postmitotic neuroblasts (NBs), revealing a stage-specific bottleneck in the neurogenic trajectory. Voluntary running reduced NB accumulation by restoring the progression through this developmental impasse, allowing neuronal maturation to be resumed. Notably, this effect involved a significant reduction of apoptosis at the NB stage. Together, these findings identify a reversible apoptotic checkpoint that contributes to age-related neurogenic decline and highlight postmitotic NBs as a key regulatory cell state capable of integrating pro-maturational signals to control the neurogenic output.

neuroscience↗

bioRxiv2025

The Translational Landscape of Reactive Astrocytes Reveals the Impact of eIF2B-mediated Dysregulation in VWM Disease

A devastating genetic recessive neurodegenerative disorder, Vanishing White Matter Disease (VWMD), stems from mutations in eIF2B--a master regulator of mRNA translation initiation and mediator of cellular stress response. While astrocytes, the brains essential support cells, are known to be central to VWMD pathology, the molecular mechanisms underlying their dysfunction remain poorly understood. Our study reveals that even a mild mutation in eIF2B5 profoundly disrupts astrocyte mRNA translation regulation upon cytokine-mediated activation, affecting nearly one-third of all expressed genes. Through innovative integration of RNA-seq and Ribo-seq analyses using primary cell cultures of astrocytes isolated from eIF2B5R132H/R132H mice, we discovered attempts to compensate for impaired protein production by increasing mRNA levels. However, this compensation proves insufficient to maintain critical cellular functions. Our comprehensive analysis uncovered significant disruptions in cellular energy production and protein synthesis machinery. We also predicted previously unknown defects in cholesterol biosynthesis within mutant astrocytes. Moreover, a meta-analysis of translation initiation scores pinpointed, for the first time, a short list of specific effector gene candidates that may drive disease progression. This powerful combination of transcriptome and translatome illuminates the complex pathophysiology of VWMD and identifies promising new biomarkers and therapeutic target opportunities.

molecular biology↗

bioRxiv2025

Audiovisual gamma stimulation enhances hippocampal neurogenesis and neural circuit plasticity in aging mice

Gamma oscillations are disrupted in various neurological disorders, including Alzheimers disease (AD). In AD mouse models, non-invasive audiovisual stimulation (AuViS) at 40 Hz enhances gamma oscillations, clears amyloid-beta, and improves cognition. We investigated mechanisms of circuit remodeling underlying these restorative effects by leveraging the sensitivity of hippocampal neurogenesis to activity in middle-aged wild-type mice. AuViS increased progenitor cell proliferation, neuronal differentiation and morphological maturation of newborn granule cells, promoting their synaptic integration. While visual or auditory stimuli alone induced dendritic growth, axonal changes required combined audiovisual stimulation. The actions of AuViS involved neurotrophin pathways, as shown by the lack of effect upon TrkB signaling blockade. These results reveal widespread plasticity mechanisms triggered by AuViS, a therapeutic approach currently proposed for treating neurological disorders in humans.

neuroscience↗

bioRxiv2022

Molecular diversity and connectivity of accessory olfactory system neurons

Olfaction is the primary sensory modality by which most vertebrate species interpret environmental cues for appropriate behavioral outputs. The olfactory system is subdivided into main (MOS) and accessory (AOS) components which process volatile and non-volatile cues. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the AOS which is largely comprised of the peripheral vomeronasal organ (VNO), the accessory olfactory bulb (AOB) and the medial subnucleus of the amygdala (MeA), we studied the molecular diversity and neuronal subtype connectivity of this interconnected circuit. We show that populations of neurons of the AOS can be molecularly subdivided based on their current or prior expression of the transcription factors Foxp2 or Dbx1. We show that the majority of AOB neurons that project directly to the MeA are of the Foxp2-lineage. Using single cell patch clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the relative contributions of excitatory and inhibitory inputs to MeA Foxp2-lineage neurons differ between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons and lineage- and sex-differences in patterns of connectivity.

neuroscience↗

bioRxiv2020

Leukodystrophy resembling Vanishing White Matter Disease is recapitulated by brain-specific depletion of apoptosis regulator MCL-1

Neurologic disorders often disproportionately affect specific brain regions, and different apoptotic mechanisms may contribute to white matter pathology in leukodystrophies or gray matter pathology in poliodystrophies. We previously showed that neural progenitors that generate cerebellar gray matter depend on the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in these progenitors produces spontaneous apoptosis and cerebellar hypoplasia, while similar conditional deletion of Mcl-1 produces no phenotype. Here, we show that, in contrast, postnatal oligodendrocytes depend on MCL-1. We found that brain-wide Mcl-1 deletion caused apoptosis specifically in mature oligodendrocytes while sparing astrocytes and oligodendrocyte precursors, resulting in impaired myelination and progressive white matter degeneration. Disabling apoptosis through co-deletion of Bax or Bak rescued white matter degeneration, implicating the intrinsic apoptotic pathway in Mcl-1-dependence. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mouse model of the leukodystrophy vanishing white matter disease (VWMD), suggesting the potential for MCL-1 deficiency to contribute to clinical neurologic disease. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 deficiency in white matter pathology, and suggest apoptosis inhibition as a leukodystrophy therapy.

neuroscience↗

bioRxiv2019

Splice donor site sgRNAs enhance CRISPR/Cas9-mediated knockout efficiency

CRISPR/Cas9 enables the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks. In most cases the DSB is repaired by non-homologous end joining, resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, these mutations do not produce the desired null result in all cases, but instead generate a similar, functionally active protein. This effect could limit the therapeutic efficiency of gene therapy strategies based on abrogating oncogene expression, and therefore needs to be considered carefully. If there is an acceptable degree of efficiency of CRISPR/Cas9 delivery to cells, the key step for success lies in the effectiveness of a specific sgRNA at knocking out the oncogene, when only one sgRNA can be used. This study shows that the null effect could be increased with an sgRNA targeting the splice donor site (SDS) of the chosen exon. Following this strategy, the generation of null alleles would be facilitated in two independent ways: the probability of producing a frameshift mutation and the probability of interrupting the canonical mechanism of pre-mRNA splicing. In these contexts, we propose to improve the loss-of-function yield driving the CRISPR system at the SDS of critical exons.

molecular biology↗